Despite continued improvements in diagnosis, surgical techniques, and radiation protocols, the available treatments for high-grade malignant glioma are grossly inadequate. The median survival time for most patients with high-grade gliomas is on the order of months. Metastatic tumors with a tropism for the CNS such as lung and breast pose an even greater problem. These tumors are five times more common than primary CNS tumors and have an equally devastating prognosis. Because surgery is the only therapy currently available that provides some benefit for these patients, the development of a potent adjuvant to surgery could indeed tip the balance towards a better outcome. Such an adjuvant would need to target micropopulations of ceils that are missed by gross surgical resection. One approach that has given promising results in preclinical animal studies and that has shown some success in clinical trials is the use of oncolytic viruses for treatment of brain tumors. A recent addition to the list of viruses that are being considered for oncolytic therapy is Vesicular stomatitis virus (VSV). Based on encouraging preliminary data, this proposal is designed to evaluate the application of recombinant VSVs (rVSVs) for the treatment of high-grade gliomas. The goal of this phase I STTR application is to obtain proof-of-principal data on the utility of VSV-based Vectors to reduce tumor-burden in a rodent model for gliomas. Aim I will evaluate the efficacy and specificity of tumor targeting by VSV in a novel, ex vivo organotypic brain slice culture system developed by scientists at the University of Tennessee Health Science Center. Our working hypothesis is that VSV will preferentially infect and kill tumor cells over cells derived from normal tissues in the organotypic culture system due to defects in the anti-viral responses of the tumor cells. Aim II will examine the efficacy and safety of VSV anti-rumor cytolytics in an in vivo intracranial glioma model. Together these studies will provide critical proof-of-concept data, which will lead to more detailed studies using glioma-specific targeting vectors.